From 1979 to 1993 there was, on average, less than a single indigenous human rabies case in the United States per annum. However, beginning in 1994 there has been a jump in the number of rabies cases that originated in the US. Moreover, the majority of the 20 human rabies cases reported in the US since 1994 have only been identified post-mortem and a history of exposure to a rabid animal has been absent. The unusually cryptic nature of these cases argues that the actual number of rabies cases in the US may be much higher than is actually reported and that a new form of rabies may be emerging. Alternatively, these cases may represent a form of rabies that has long existed but has been overlooked. The etiological agent of most of these cases has been demonstrated to be a rabies virus variant that circulates in silver-haired bats and is genotypically and phenotypically distinct from those strains, found in terrestrial animals, that are generally associated with human rabies. The migratory territory of the silver-haired bat includes all of North America and is consistent with the fact that cryptic rabies cases have appeared throughout the US. To more accurately determine the frequency of cryptic rabies in the US and to determine whether this is a recently emergent disease, we propose a retrospective study of pathological specimens collected from patients that have died of acute encephalitis of unknown origin. We have established collaborations with four neuropathology centers in Little Rock, New York, and Philadelphia to provide us with brain tissue sections from appropriate patients. These sections will be analyzed in our laboratory by immunohistochemistry and RT-PCR for evidence of rabies virus. If positives are obtained, material will provided to the CDC for independent confirmation of the results.